The Assembly did have some limited interaction with Vulcans before the 2150s and made first contact with a Human vessel, Enterprise, in 2152. This early Human interaction with the Tholians led to conflict as the Tholians gained knowledge that Enterprise was in possession of future technology, which they tried to steal. The Tholian Assembly's interest in time travel was indicative of their suspected involvement in a larger conflict, the Temporal Cold War. Though they were a party in the attempted stealing of the futuristic shuttle, they did not actually harm or try to harm the Vulcans or the Enterprise crew. (ENTepisode: "Future Tense")

First contact between the Assembly and the Federation was made by the USS Intrepid, which was performing a deep space charting mission near the disputed Tholian border. The commanding officer of the Federation starship was warned by the Tholians to leave the area immediately, after which CaptainSpiak of the Intrepid complied, whereupon he informed Starfleet Command of the encounter. Several weeks later, a transmission from the Tholians demanded an audience with Captain Spiak at the border line as the Assembly thought it was prudent to learn more about the nature of a possible enemy. (TOSreference: The Worlds of the Federation)

Relations between the Assembly and Humanity did not improve after this first hostile encounter. By the 23rd century, the Tholians were involved in frequent conflicts with the United Federation of Planets in their expansionist programs. The Tholians, who have a non-humanoid makeup incompatible with environments humanoids occupy, were known during this era to employ shock troops of cultures they had conquered or conscripted into their service. One of the most feared of the Tholians' enforcers were the Chakuun species. (EVcomic: "Flesh of My Flesh")

Ongoing conflict with the Federation was finally brought to an end in 2254 when there was a revelation regarding the differences in the way the two powers measured borders and territory. (EVcomic: "The Fallen")

Formal diplomatic ties were eventually formed between the Assembly and the Federation, and a Tholian diplomatic delegation was stationed on Starbase 47 as early as 2265. (VANnovel: Harbinger)

It is unclear what, if any, relationship existed between the 23rd century Tholians and their 22nd century mirror universe counterparts. The temporal nature of such a relationship might imply this is yet another tangle in the web of the Temporal Cold War.

In 2271, the Federation made a formal announcement in recognition of ongoing diplomatic ties between the two powers. (STreference: Star Charts)

Ongoing contact with the Federation was minimal. The Assembly rarely contacted the Federation, but they did slow their expansion and ceased encroaching on Federation territory. Better relations between the Assembly and the Federation opened in 2298, after the Federation intervened in a conflict between the Tholians and the Neyel Hegemony being conducted over extradimensional tunnels between the Milky Way Galaxy and the Small Magellanic Cloud created by the interphasic rift. (TLEnovel: The Sundered)

Tholian space was violated in 2367 when a doomsday machine under the command of a woman known as Delcara entered their territory in order to "devour" worlds within their space to power the weapon. Attempts were made to stop her, but even the infamous Tholian web weapon was incapable of halting the behemoth. Fortunately it was stopped thanks to the assistance of the crew of the USS Enterprise-D. (TNGnovel: Vendetta)

In 2373, the Tholian Assembly signed a non-aggression pact with the Dominion, and stayed uninvolved through the entirety of the Dominion War. (DS9episode: "Call to Arms") This combined with the tenuous peace they had with the Federation meant that the Assembly were content with observing the war. However, whilst an unpopular opinion publicly, some believed that the Tholians would have fallen before the superior might of the Dominion had the Founders not been defeated. (SCEeBook: Interphase, Part One)

In 2376, the Defiant reappeared. The USS da Vinci was sent to retrieve it, and several Tholian starships oversaw it. However, when proof that they had performed the massacre at Taelus was discovered, the Tholian Assembly ordered the destruction of the da Vinci. They were fought off and forced to retreat however, by the joint powers of the da Vinci and the Defiant. SCEeBook: Interphase)

This appears, at first glance, to contradict ENTepisode: "In a Mirror, Darkly", in which the Defiant is transported to the mirror universe and captured by the Terran Empire. However, the authors of the Interphase SCE stories are currently collaborating with "In a Mirror, Darkly" writer Mike Sussman to create an ENT-era mirror universe story that will be a sequel to "Darkly," suggesting a possibility that this story arc will be closed, reconciling the two stories' endings.